The present invention relates to a sulfonamide-containing indole compound and to an antiangiogenic effect thereof. More particularly, it relates to an antitumor agent, a cancer metastasis suppressor, a therapeutic agent for diabetic retinopathy, a therapeutic agent for rheumatic arthritis and a therapeutic agent for hematoma on the basis of an antiangiogenic effect.
It has become clear that there is a close relation between proliferation of cancer and angiogenesis. Thus, when angiogenesis is not generated at the site of cancer, the cancer remains in a state of dormant tumor. However, it has become clarified that, when angiogenesis is generated, oxygen and nutrients in blood are supplied to the tumor whereby proliferation and metastasis of cancer are promoted resulting in a clinically malignant state. Accordingly, it is expected that, when angiogenesis of cancer is suppressed, proliferation and metastasis of cancer can be suppressed. Since angiogenetic vessels are composed of endothelial cells and interstitial cells of the host, target of the antiangiogenic agent is not cancer cells but such normal cells of the host. Because of the fact that the cancer cells are not a direct target, efficacy to the cancer which does not respond to known anticancer agents can be expected as well and, in addition, it is presumed that the possibility of occurrence of tolerant cancer which is a big problem in cancer therapy is little. In addition, angiogenesis is a tumor-specific phenomenon and, in mature individuals, it is limited to the formation of endometrium, etc. accompanied by a menstrual cycle. Accordingly, its adverse effect is thought to be little as compared with known anticancer drugs. Recently, it has been experimentally proved in preclinical tests that antiangiogenic agents are able to suppress and further to reduce the proliferation of cancer in the cancer-transplanted models and that tolerant cancer is not generated and, in clinical tests, the correlation between angiogenesis and malignization of many solid cancers such as breast cancer, prostatic cancer, lung cancer and cancer of the colon has been shown.
In cancer tissues, apoptosis and proliferation of cancer cells continuously occur and it has been known that, depending upon the balance between them, progressive cancer or dormant tumor results. An antiangiogenic agent does not directly kill the cancer cells but cuts off the nutrient sources so that the said balance is inclined to apoptosis inducing dormant tumor or reduction in cancer whereby it is a drug which can be expected to exhibit an excellent effect (prolongation of life, inhibition of recurrence and suppression of metastasis) by a long-term therapy.
In a preclinical stage, there are antiangiogenic agents by various action mechanisms but, since their antitumor effect in a preclinical stage is insufficient, their usefulness in clinical stage is still doubtful and, therefore, there has been a brisk demand for antiangiogenic agents where the effect is reliable.
It has been also known that angiogenesis participates in retinopathy or retinitis. When blood vessel is proliferated in retina, eyesight gets worse and, when progressed, blindness is resulted. There has been no effective therapeutic drug therefor at present and effective therapeutic drugs have been demanded.
WO 9301182 discloses antitumor agents due to a specific tyrosine kinase inhibiting activity of the compounds having an indole skeleton but they are indolylmethylene-2-indolinone compounds and are different from the present invention. Similarly, WO 964016 discloses an antitumor agent due to a specific tyrosine kinase inhibiting activity of the compounds having an indole skeleton but they are 2-indolinone-3-methylene compounds and are different from the present invention. Sulfonamide compounds having an indole structure are disclosed in JP-A 7-165708 and JP-A 8-231505. However, the compounds which are specifically disclosed in JP-A 7-165708 and have two substituents other than aryl (or heteroaryl) sulfonylamino group on an indole ring are limited and combinations of those substituents are only six, i.e. (1) 3-Cl and 4-Cl; (2) 3-Cl and 4-OCH3; (3) 3-Cl and 4-OH; (4) 3-Cl and 4-CH3; (5) 3-Cl and 4-CN; and (6) 3-CN and 5-Br. There is no combination of (a) 3-CN and 4-CH3; (b) 3-Cl and 5-Br; (c) 3-Cl and 4-Br; and (d) 3-Br and 4-CH3. With regard to 4-halogen monosubstituted compounds, there is a description for 4-Br compounds but its sulfonyl moiety is a p-nitrophenol compound only. Further, indole compounds disclosed in JP-A 8-231505 are 3-halogen or 3-cyano monosubstituted compounds only. In those laid-open publications, there is no description for an antiangiogenic effect at all and there is no description suggesting that as well.
An object of the present invention is to create a novel antiangiogenic agent and to provide an antitumor agent which shows a high safety and a sure effect as compared with conventional antitumor agents and is able to be administered for a long period.
The present inventors have carried out an intensive study, found that the sulfonamide-containing indole compound represented by the following formula achieves the aimed object and accomplished the present invention. That is, the present invention relates to a sulfonamide-containing indole compound represented by the following formula (I), its pharmacologically acceptable salt or hydrates thereof. 
In the formula, R1 represents hydrogen atom, a halogen atom or cyano group; R2 and R1 are the same as or different from and each represents hydrogen atom, a C1xcx9cC4 lower alkyl group or a halogen atom; R4 represents hydrogen atom or a C1xcx9cC4 lower alkyl group; and the ring A represents cyanophenyl group, aminosulfonylphenyl group, aminopyridyl group, aminopyrimidyl group, halopyridyl group or cyanothiophenyl group, provided that the case where all of R1, R2 and R3 are hydrogen atoms, where both R2 and R3 are hydrogen atoms, or where the ring A is aminosulfonyl group and both R1 and R2 are halogen atoms is excluded. Further, when the ring A is cyanophenyl group, 2-amino-5-pyridyl group or a 2-halo-5-pyridyl group and R1 is cyano group or a halogen atom, at least one of R2 and R3 should not be a hydrogen atom.
The present invention relates to a method for the prevention or therapy of the disease against which inhibitory of angiogenesis at the site of tumor, rheumatic arthritis or diabetic retinopathy is effective for the prevention or therapy, by administering a pharmacologically effective dose of the above-mentioned indole compound, its pharmacologically acceptable salt or hydrates thereof to a patient.
The present invention further relates to a use of the above-mentioned indole compound, its pharmacologically acceptable salt or hydrates thereof for the manufacture of a preventive or therapeutic agent for the disease against which an antiangiogenic agent is effective for the prevention or therapy.
The present invention furthermore relates to an antiangiogenic agent, an antitumor agent, a therapeutic agent for pancreatic cancer, a therapeutic agent for cancer of the colon, a therapeutic agent for gastric cancer, a therapeutic agent for breast cancer, a therapeutic agent for prostatic cancer, a therapeutic agent for lung cancer, a therapeutic agent for ovarian cancer, a cancer metastasis suppressor, a therapeutic agent for diabetic retinopathy, a therapeutic agent for rheumatic arthritis or a therapeutic agent for hematoma, which comprises the above-mentioned indole compound, its pharmacologically acceptable salt or hydrates thereof as an effective ingredient. It relates to a method for prevention, therapy and improvement by use of any of those pharmaceutical agents. Further, it relates to a use of the above compound for the manufacture of any of those pharmaceutical agents.
In the above formula (I), a halogen atom means fluorine atom, chlorine atom, bromine atom or iodine atom. A C1xcx9cC4 lower alkyl group means a linear or branched alkyl group such as methyl group, ethyl group, n-propyl group, n-butyl group, iso-propyl group, iso-butyl group and tert-butyl group.
The indole compound represented by the above formula (I) may form a salt with an acid or with a base. The present invention also includes a salt of the indole compound (I) as well. Examples of the salt with an acid are an inorganic acid salt such as hydrochloride, hydrobromide or sulfate and that with an organic acid such as acetic acid, lactic acid, succinic acid, fumaric acid, maleic acid, citric acid, benzoic acid, methanesulfonic acid or p-toluenesulfonic acid. Examples of the salt with a base are an inorganic salt such as sodium salt, potassium salt or calcium salt and that with an organic base such as triethylamine, arginine or lysine.
It goes without saying that all hydrates of such a compound and of its pharmacologically acceptable salt are included. Although the compounds of the present invention show a strong antiangiogenic effect, compounds which are subjected to metabolism such as oxidation, reduction, hydrolysis and conjugation in vivo are also included. The present invention further includes the compounds which produce the compound of the present invention as a result of metabolism such as oxidation, reduction and hydrolysis in vivo.
The compound of the present invention (I) can be manufactured by various methods and representative ones among them will be as follows.
It can be manufactured by the reaction of a sulfonic acid represented by the formula (II): 
(in the formula, the ring Aa represents cyanophenyl group, aminosulfonylphenyl group, aminopyridyl group, aminopyrimidyl group, a halopyridyl group or cyanothiophenyl group) or a reactive derivative thereof with a compound represented by the formula (III): 
(in the formula, R1a represents hydrogen atom, a halogen atom or cyano group; and R2a and R3a are the same as or different from and each represents hydrogen atom, a C1xcx9cC4 lower alkyl group or a halogen atom, provided that the case where all of R1a, R2a and R3a are hydrogen atoms or where both R2a and R3a are hydrogen atoms is excluded).
Examples of the reactive derivative of the sulfonic acid (II) are commonly and well utilized reactive derivatives such as sulfonyl halide, sulfonyl acid anhydride and N-sulfonylimidazolide and the particularly advantageous example is a sulfonyl halide. Although there is no particular limitation for the solvent used for the reaction, those which dissolve the material substances and do not readily react with them are preferred. For example, pyridine, tetrahydrofuran, dioxane, benzene, ethyl ether, dichloromethane, dimethylformamide and a mixed solvent consisting of two or more which are selected from them can be used. In addition, when an acid is liberated with a progress of the reaction as in the case of using a sulfonyl halide in the reaction, it is preferred to conduct the reaction in the presence of an appropriate deacidifying agent and, therefore, the use of a basic solvent such as pyridine is particularly appropriate. When a neutral solvent is used, a basic substance such as an alkali carbonate or an organic tertiary amine may be added. of course, the solvent which can be used is not limited to those listed here. Usually, the present reaction proceeds at room temperature but, if necessary, it may be cooled or heated. The reaction time is usually from 10 minutes to 20 hours and is optionally selected depending upon the type of the material compounds and the reaction temperature.
When an amino group is protected in the resulting product, a conventional deprotecting method such as treatment with an acid, treatment with an alkali and catalystic reduction may be carried out upon necessity whereby it is possible to give an indole compound (I) having a free amino group.
Now, methods for the manufacture of the starting compounds (II), reactive derivative thereof and (III) used in the present invention will be illustrated.
The starting compound (II) and reactive derivative thereof include both known compounds and novel compounds. In the case of novel compounds, they can be manufactured by applying the already-reported synthetic method for known compounds or by combining them. For example, novel sulfonyl chloride may be manufactured by a method applying the synthetic methods mentioned in Chem. Ber., 90, 841 (1957); J. Med. Chem., 6, 307 (1963); J. Chem. Soc. (c), 1968, 1265; Chem. Lett., 1992, 1483; J. Am. Chem. Soc., 59, 1837 (1937); J. Med. Chem., 23, 1376 (1980); J. Am. Chem. Soc., 70, 375 (1948); J. Am. Chem. Soc., 78, 2171 (1956) etc.
When R1a and R3a are hydrogen atoms and R2a is a halogen atom in the starting compound (III), it can be manufactured by a known synthetic method. When R2a and R3a are the same as or different from and each represents hydrogen atom, a C1xcx9cC4 lower alkyl group or a halogen atom (the case where both are hydrogen atoms is excluded) and R1a is cyano group, it can be manufactured as follows.
Reaction Formulae 1 
In the formulae, R1a, R2a and R3a have the same meanings as defined above.
Reaction Formulae 2 
In the formulae, R1a, R2a and R3a have the same meanings as defined before; and DPPA means diphenyl phosphoryl azide.
When R1a is a halogen atom, it can be manufactured in such a manner that the formula (a) or the formula (g) in the above-mentioned reaction formulae (1) and (2) is halogenated by a conventional means and the nitro group is reduced or a protecting group of an amino group is eliminated.
When the compound of the present invention is used as a medicament, it is administered either orally or parenterally. The dose varies depending upon degree of the symptom, age, sex, body weight and sensitivity difference of the patient, method of the administration, period for the administration, interval of the administration, property of the pharmaceutical preparation, type of the preparation, type of the effective ingredients etc., and is not particularly limited. In the case of intravenous administration, it is 1-2000 mg, preferably 1-1500 mg and, more preferably, 5-1000 mg while, in the case of oral administration, it is usually 10-6000 mg, preferably about 50-4000 mg and, more preferably, 100-3000 mg per day for adults, and that is usually administered once daily or by dividing into up to three times a day.
When a solid preparation for oral administration is prepared, filler and, if necessary, binder, disintegrating agent, lubricant, coloring agent, corrigent, etc. are added to the main ingredient, followed by subjecting to a common method to make into tablets, coated tablets, granules, fine granules, powders, capsules etc.
Examples of the filler are lactose, corn starch, sucrose, glucose, sorbitol, crystalline cellulose and silicon dioxide; examples of the binder are polyvinyl alcohol, ethyl cellulose, methyl cellulose, gum arabic, hydroxypropyl cellulose and hydroxypropyl methyl cellulose; examples of the lubricant are magnesium stearate, talc and silica; examples of the coloring agent are those which are allowed to add to the pharmaceuticals; and examples of the flavoring agents are cacao powder, menthol, aromatic, peppermint oil, borneol, and cinnamon powder. It is of course no problem that such tablets and granules are appropriately coated with a sugar coat, gelatin coat or others if necessary.
In preparing the injection, a pH adjusting agent, a buffer, a suspending agent, a solubilizer, a stabilizer, an isotonizing agent, a preservative, etc. are added, if necessary, to the main ingredient followed by subjecting to a conventional method to make into injections for intravenous, subcutaneous or intramuscular administration. At that time, it may be made into a freeze-dried product by a common method if necessary.
Examples of the suspending agent are methyl cellulose, polysorbate 80, hydroxyethyl cellulose, gum arabic, tragacanth powder, sodium carboxymethyl cellulose and polyoxyethylene sorbitan monolaurate.
Examples of the solubilizer are polyoxyethylene hydrogenated castor oil, polysorbate 80, nicotinamide, polyoxyethylene sorbitan monolaurate, macrogol and castor oil fatty acid ethyl ester.
Examples of the stabilizer are sodium sulfite and sodium metasulfite. Examples of the preservative are methyl para-hydroxybenzoate, ethyl para-hydroxybenzoate, sorbic acid, phenol, cresol and chlorocresol.